It has been demonstrated that part of the function of the immune system is elimination of tumors (Steer, et al. (2010) Oncogene 29:6301-13; de Visser & Coussens (2006) Contrib. Microbiol. 13:118-37; Lollini, et al. (2006) BMC Bioinformatics 7:352). Almost without exception, any tumor that manifests clinically has evaded immune surveillance by developing multiple immunosuppression mechanisms, such as expressing immunosuppressive mediators or calling in immunosuppressive cells with chemoattractants (Zou, et al. (2005) Nat. Rev. Cancer 5:263-74; Cubillos-Ruiz, et al (2009) J. Clin. Invest. 119:2231-44; Cubillos-Ruiz, et al. (2009) Future Oncol. 5:1189-92; Cubillos-Ruiz, et al. (2010) Cell Cycle 9:260-8; Scarlett, et al. (2009) Cancer Re. 69:7329-37; de Visser & Coussens (2006) supra; Conejo-Garcia, et al. (2004) Cancer Res. 64:2175-82; Conejo-Garcia, et al. (2003) Cancer Biol. Ther. 2:446-51; Conejo-Garcia, et al. (2005) Blood 105:679-81). Supporting ongoing anti-tumor immune responses offers great promise to complement treatments targeting the tumor cell cycle or cellular signaling pathways, and already represent the most effective intervention against otherwise incurable melanomas (Dudley, et al. (2001) J. Immunother. 24:363-73; Rosenberg & Dudley (2004) Proc. Natl. Acad. Sci. USA 101:14639-45; Zitvogel & Kroemer (2009) J. Clin. Invest. 119:2127-30). However, it has become increasingly clear that effective strategies to break tumor-mediated immunosuppression will be required to elicit comparable protective anti-tumor immunity against the most lethal cancers. This is because effective antitumor T cell responses mediated by CD4 and CD8 T-cells are not effectively activated in immune-suppressed tumor environments unless the immunosuppression can be reversed.
Immunotherapies are of particular interest for dealing with metastatic disease since the immune system is uniquely capable of identifying and eliminating small undetectable metastases. Ovarian carcinoma is a particularly promising target for novel immunotherapies in this context for a variety of reasons. First, ovarian cancer is typically diagnosed at an advanced stage as a metastatic disease with very poor prognosis. Second, multiple independent studies have confirmed that the magnitude of spontaneous but obviously suboptimal anti-tumor immune responses can predict the outcome of ovarian cancer patients (Hamanishi, et al. (2007) Proc. Natl. Acad. Sci. USA 104:3360-5; (Sato, et al. (2005) Proc. Natl. Acad. Sci. USA 102:18538-43; Zhang, et al. (2003) Zhonghua Zong Liu Za Zhi 25:264-7; Zhang, et al. (2003) N. Engl. J. Med. 348:203-213). Third, the 5-year survival rates of ovarian cancer patients have changed very little after 30 years targeting almost exclusively the tumor cell cycle, which urgently demands new complementary interventions. Fourth, even at a metastatic stage, ovarian cancer is most frequently found as a disease compartmentalized in the peritoneal cavity, which facilitates the adoptive transfer of immune cells or the application of adjuvants directly in the tumor microenvironment. Unfortunately, multiple immunosuppressive mechanisms converge at ovarian cancer locations to eventually abrogate both ongoing anti-tumor immunity and the effect of adoptively transferred tumor-reactive lymphocytes (Zou (2006) Nat. Rev. Immunol. 6:295-307; Nesbeth & Conejo-Garcia (2010) Clin. Dev. Immunol. 2010:139304; Kryczek, et al. (2007) Am. J. Physiol. Cell Physiol. 292:C987-95; Kryczek, et al. (2007) J. Immunol. 178:6730-3). Some of the most powerful immunosuppressive networks are orchestrated by regulatory T cells (Curiel, et al. (2004) Nat. Med. 10:942-9), as well as a variety of myeloid cells with overlapping phenotypic attributes of various lineages (Cubillos-Ruiz, et al. (2009) J. Clin. Invest. 119:2231-44; Scarlett, et al. (2009) supra; Curiel, et al. (2003) Nat. Med. 9:562-7; Huarte, et al. (2008) Cancer Res. 68:7684-91). In the microenvironment of solid ovarian tumor masses in both mice and humans, studies have identified massive recruitment of leukocytes with predominant phenotypic attributes of immature dendritic cells (DCs), including the expression of DEC205, CD11c, MHC-II, and CD8α. While these immature DC are immune-suppressed by the ovarian tumor, they possess the ability to phagocytose antigen in their tumor environment, and acquire the capacity to effectively present processed antigens in the right milieu (Cubillos-Ruiz, et al. (2009) supra; Scarlett, et al. (2009) supra). However, rather than boosting adaptive immune responses, ovarian cancer-associated DCs are not activated to mature, are strongly immunosuppressive, and support blood vessel formation, which promotes tumor development (Cubillos-Ruiz, et al. (2009) supra; Scarlett, et al. (2009) supra; Huarte, et al. (2008) supra). Adjuvant therapy that could mediate the maturation of these immature dendritic cells would reverse the immunosuppression and foster immunostimulation for therapeutic purposes. Such an approach could be used as a primary immunotherapy, as a conditioning therapy for adoptive T cell therapy, or as a therapy to boost T-cell antitumor responses.
The immune system has evolved to recognize and respond to microorganisms and therefore, microorganisms or their constituents are powerful adjuvants (Rakoff-Nahoum & Medzhitov (2009) Nat. Rev. Cancer 9:57-63). Each microorganism has unique characteristics in how they interact with the immune system and therefore each microorganism has unique adjuvant characteristics. Recently, the rapidly developing understanding about the interaction of innate and adaptive immunity and the associated understanding of how adjuvants work has fostered renewed interest in using microorganisms as adjuvants to stimulate antitumor immune responses (Paterson & Maciag (2005) Curr. Opin. Mol. Ther. 7:464-60; Paterson (2004) Immunol. Res. 27:451-62; Paterson & Ikonomidis (1996) Curr. Opin. Immunol. 8:664-9; Pan, et al. (1995) Nat. Med. 1:471-7; Pan, et al. (1995) Cancer Res. 55:4776-9; Pan, et al. (1999) Cancer Res. 59:5264-9; Sinnathamby, et al. (2009) J. Immunother. 32:856-69). This approach is strengthened by the ability to genetically manipulate the microorganisms to make them safer and more effective (Paterson & Ikonomidis (1996) supra). The focus of these studies has been on using Listeria monocytogenes, a gram positive bacterium that can live either within or outside of cells (Paterson & Maciag (2005) supra; Paterson (2004) supra; Paterson & Ikonomidis (1996) supra; Pan, et al. (1999) supra; Pan, et al. (1995) supra; Sinnathamby, et al. (2009) supra). Attenuated Listeria has been used in multiple phase I and II clinical trials against cervical, and prostate cancers (ClinicalTrial.gov Identifier NCT01116245, NCT00327652, NCT00585845, NCT0080007).